Treatment of agnogenic myeloid metaplasia with danazol: A report of four cases

Peripheral cytopenias are common in patients with agnogenic myeloid metaplasia (AMM). They are an important cause of morbidity and mortality, and their treatment is difficult. We report on 4 patients with AMM and severe cytopenia treated with danazol (400–600 mg/day). Three of them became independent of red blood cell (RBC) transfusion, while the other had a slight reduction in RBC requirement. In addition, correction of thrombocytopenia and disappearance of splenomegaly were observed in 1 and 2 patients, respectively. No side effects were observed. In our experience, danazol appears effective and safe in the subset of patients with AMM whose disease is mainly characterized by bone-marrow failure. These data warrant further studies to evaluate this treatment and explore its mechanism of action. © 1996 Wiley-Liss, Inc.     

Sarcoidosis and agnogenic myeloid metaplasia

Abstract. Agnogenic myeloid metaplasia (AMM) was recognized 3 years after a diagnosis of sarcoidosis in a 45-year-old man. This is the second reported instance of that association, and the 15th reported case in which systemic granulomata have been associated with a myeloproliferative disorder (MPD). In the client population at risk, this connection would be expected to occur by chance once in 1700 years. Therefore, it is unlikely that the association is fortuitous. Systemic granulomata may represent an immunologic response to antigens of neoplastic origin in MPD     

Pericardial tamponade associated with myeloid metaplasia

A 32-year-old white male with agnogenic myeloid metaplasia developed pericardial tamponade shortly after elective splenectomy. Tamponade was relieved by pericardiocentesis but recurred, necessitating partial pericardiectomy. Following surgery and a course of radiation therapy to the heart, there was no further significant reaccumulation of fluid. Pathologic evaluation demonstrated foci of extramedullary hematopoiesis in the pericardium. To our knowledge, pericardial tamponade has not previously been reported as a biopsy-proven complication of myeloid metaplasia.     

Allogeneic bone marrow transplantation for agnogenic myeloid metaplasia

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 × 10⁹/l and platelet count > 50 × 10⁹/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.     

Plasma matrix metalloproteinase and tissue inhibitor of metalloproteinase in patients with agnogenic myeloid metaplasia or idiopathic primary myelofibrosis

Agnogenic myeloid metaplasia (AMM) is characterized by bone marrow fibrosis with abnormal accumulation of extracellular matrix components (ECM), which is dependent on the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Twenty-five patients with AMM, 30 with essential thrombocythemia (ET), 12 with polycythemia vera (PV) and 20 normal control subjects were studied. AMM patients had decreased plasma levels of MMP-3 and marked elevated levels of TIMP-1, but MMP-1, MMP-2 and MMP-9 levels were not significantly different from control subjects. Elevated levels of plasma TIMP-1, but not MMPs, were found in ET and PV. Reduced MMP activity together with increased TIMP-1 activity may be essential in fibrosis formation.     

Radiation therapy for symptomatic hepatomegaly in myelofibrosis with myeloid metaplasia

OBJECTIVE: To describe the experience with liver irradiation in advanced cases of myelofibrosis with myeloid metaplasia (MMM). METHODS: Over a 20-yr period, 14 patients with MMM were treated with a total of 25 courses of liver, abdominal, or abdominal and pelvic irradiation for symptomatic hepatomegaly with (5 patients) or without (9 patients) ascites. All 14 patients had advanced disease and 11 (79%) had previous splenectomy. The median radiation therapy (RT) dose per course was 150 cGy (range 50-1000) administered at a median of six fractions. Four patients received two to six courses. RESULTS: Twelve of the 14 patients (86%) had a transient (median 3 months) subjective response from RT. However, in only 35% of these was there a transient (median 3 months) decrease in palpable liver size. Four of the five patients with ascites experienced a short-term response from RT. Eight of the 13 patients suitable for evaluation (62%) had treatment-associated cytopenia, often in the form of anemia and/or thrombocytopenia. At last follow-up, 10 patients (71%) had died after a median of 7 months (range 0.1-23) and 4 were alive at 3, 20, 33, and 57 months after RT. CONCLUSIONS: Low-dose abdominal RT for symptomatic hepatomegaly or ascites associated with advanced-stage MMM is myelosuppressive and provides only temporary and mainly subjective and short-lived relief.     

Myelofibrosis with myeloid metaplasia in adult individuals 30 years old or younger: presenting features, evolution and survival

Myelofibrosis with myeloid metaplasia (MMM) usually affects older people and is associated with a median survival of 3.5-5 yr. Survival of MMM patients 55 yr old or younger is longer, but there is no information on the youngest subset. The presenting features, evolution and survival were analyzed in 9 patients with MMM aged 30 yr or less, representing 2.8% of two series including 323 cases. Age ranged from 17 to 30 yr; 3 patients were males and 6 females. Five patients were asymptomatic and none had constitutional symptoms. Anemia was observed in 4 patients, being severe in only one. The WBC count was normal in 7 patients and 2 had mild leukocytosis; moderate thrombocytosis was observed in 7 patients. No patient showed blood blast cells or bone marrow cytogenetic abnormalities. With a median follow-up of 6.8 (range 0.8-28) yr, 2 patients died 10.7 and 9.9 yr from diagnosis, one from complications of bone marrow transplantation performed after progression of the disease and the other from gastrointestinal bleeding secondary to portal hypertension. Among remaining patients, one developed Budd-Chiari syndrome, another was lost to follow-up at 3 yr, and 5 remain asymptomatic and currently without treatment (one had been splenectomized at diagnosis). These results indicate that in most young adults with MMM the disease presents without adverse prognostic factors and may remain stable for years, which may be of interest when considering the treatment of such patients.     

Splenic irradiation for symptomatic splenomegaly associated with myelofibrosis with myeloid metaplasia

Twenty-three patients who had myelofibrosis with myeloid metaplasia (MMM) were treated at our institution with 50 courses of splenic irradiation (SI) for symptomatic splenomegaly. The median dose of radiation per course was 277.5 cGy, administered in a median of 7.5 fractions. 8/23 patients received multiple courses of SI. Of 49 evaluable courses of SI, 46 (93.9%) resulted in an objective decrease in spleen size. The median duration of response was 6 months (range 1–41). Reduction in spleen size was associated with symptomatic relief in all patients. Overall median survival after SI was 22 months. Significant cytopenia occurred in 10 (43.5%) patients, or 16 (32%) of the 50 courses of SI. Prolonged, life-threatening pancytopenia after a single course of SI occurred in six patients (26%), resulting in fatal sepsis or haemorrhage in three (13%). Nine patients underwent subsequent splenectomy; the perioperative mortality rate was 11%. One third of patients experienced postoperative intra-abdominal haemorrhage necessitating surgical re-exploration. SI can provide symptomatic relief and a reduction in spleen size in most MMM patients. The increased risk of postoperative bleeding in patients requiring subsequent splenectomy dictates against considering SI as an alternative to splenectomy for patients who are otherwise good surgical candidates.     

Hypermethylation of the P15INK4b and P16INK4a in agnogenic myeloid metaplasia (AMM) and AMM in leukaemic transformation

Hypermethylation of p15 and p16 genes was determined in 32 patients with agnogenic myeloid metaplasia(AMM), also known as idiopathic myelofibrosis (MF). These included 10 patients in leukaemic transformation phase. Using polymerase chain reaction-based methylation analysis assay methods, with substantiation using Southern blot analysis, the study showed no hypermethylation of p15 or p16 genes in the chronic phase of AMM, but p15 gene hypermethylation was found in four patients (40%) and p16 gene hypermethylation in two patients (20%) when they were in leukaemic transformation stage. Furthermore, two of the patients in leukaemic transformation were found to have both p15 and p16 gene hypermethylation, demonstrating possible multiple gene hypermethylation in the same patient. Thus, hypomethylation agents for treating patients with AMM in leukaemic transformation may be appropriate for future trials.     

Melphalan treatment in patients with myelofibrosis with myeloid metaplasia

Between January 1985 and December 1992, 104 consecutive patients with symptomatic myelofibrosis with myeloid metaplasia (MMM) [splenic enlargement >5 cm and/or transfusional requirement or Hb < 10 g/dl and/or white blood cell (WBC) count >20 x 10(9)/l and/or platelets >1.0 x 10(9)/l] received low-dose Melphalan (2.5 mg/3 times/week) to evaluate the efficacy and toxicity of this approach. Among 99 evaluable patients, 66 (66.7%) achieved a response after a median time of 6.7 months: 26 (26.3%) had a normalization of all clinical and haematological parameters (complete response, CR) and 40 (40.4%) showed an improvement >50% (partial response, PR). Thirty-three patients (33.3%) were resistant. Reversible haematological toxicity was the most common complication. Median durations of CR and PR were 28.4 and 26 months respectively: median survival of CR + PR patients was 71.2 months (95%CI: 33.8-108.7) versus 36.5 months (95%CI: 24.5-48.5) for the non-responders (log-rank test, P =0.002). In the multivariate analysis, the following variables were significantly associated with a shorter survival: anaemia [hazard risk (HR) = 2.7], WBC count >20 x 10(9)/l (HR = 2.4) and not achieving any type of response, either partial or complete (HR = 3.9). In conclusion, Melphalan could be a promising first-line option for MMM patients with clinical or haematological symptoms requiring treatment.     

Reversal of bone marrow fibrosis and subsequent development of polycythemia in patients with myeloproliferative disorders

Bone marrow fibrosis is a characteristic finding in agnogenic myeloid metaplasia and in the spent phase of polycythemia vera. It is commonly believed that the reticulin deposition is irreversible. However, we report four patients who demonstrated clinical and laboratory evidence of transition from myelofibrosis to polycythemia. The transition was documented by improvement in the hemoglobin concentration and by determination of the Cr51 red blood cell mass, accompanied by a resolution of the fibrosis on serial bone marrow biopsies. Two of the patients had been treated with alkylating agents and splenectomy, one with myelosuppressive therapy without splenectomy, and one with splenectomy alone. These findings indicate that bone marrow fibrosis in the chronic myeloproliferative disorders is not always an irreversible phenomenon. Pathogenetic implications will be discussed.     

Bone changes in myelofibrosis with myeloid metaplasia: a histomorphometric and microcomputed tomographic study

Myelofibrosis with myeloid metaplasia (MMM) is a clonal disorder of the haematopoietic stem cell which can be associated with marrow fibrosis and/or osteosclerosis. Because bone progenitors and mature bone cells are influenced by the marrow microenvironment, cellular and tissular changes were assessed by histomorphometry in MMM. Thirteen patients, with a clinical proven MMM, had a bone biopsy of the iliac crest with double tetracycline labelling and osteoclast count. Histomorphometry was done at the 2D level (bone volume, osteoid parameters, bone histodynamic parameters and osteoclast count) and 3D level by microcomputed tomography. All patients had clusters of abnormal megakaryocytes in bone marrow. Newly apposed bone packets were observed in 12 patients and corresponded to an increased thickness of some bone units with new lamellae or focal areas of woven bone anchored on the pre-existing trabeculae. Osteoid parameters were unchanged, only bone formation rate appeared considerably increased in seven patients. There was a net tendency for decrease in osteoclast number and conversion of trabecular pillars into plates. An uncoupling of bone remodelling was evidenced with an increased life-span of osteoblasts associated with a normal/reduced osteoclast activity. A very complex network of factors is candidate to explain bone changes observed in MMM.     

Cytogenetic findings and their clinical relevance in myelofibrosis with myeloid metaplasia

The prognostic significance of bone marrow cytogenetic lesions in myelofibrosis with myeloid metaplasia (MMM) was investigated in a retrospective series of 165 patients. An abnormal karyotype was demonstrated in 57% of patients. At diagnosis (n = 92), 48% of the patients had detectable cytogenetic abnormalities, and clonal evolution was frequently demonstrated in sequential studies. More than 90% of the anomalies were represented by 20q-, 13q-, +8, +9, 12p-, and abnormalities of chromosomes 1 and 7. Of these, 20q-, 13q- and +8 were the most frequent sole abnormalities, each occurring in 15-25% of the abnormal cases. Trisomy 9 and abnormalities of chromosomes 1 and 7 were equally prevalent but were usually associated with additional cytogenetic lesions. Chromosome 5 abnormalities were infrequent but were over-represented in the group of patients exposed to genotoxic therapy. In a multivariate analysis that incorporated other clinical and laboratory variables, the presence of an abnormal karyotype did not carry an adverse prognosis. Instead, +8, 12p-, advanced age and anaemia were independent prognostic determinants of inferior survival. In particular, survival was not adversely affected by the presence of either 20q- or 13q-.     

Spleen neoangiogenesis in patients with myelofibrosis with myeloid metaplasia

Neoangiogenesis is an integral component of bone marrow myeloproliferation in patients with myelofibrosis with myeloid metaplasia (MMM). As extramedullary haematopoiesis is a constitutive feature of MMM, we studied spleen neoangiogenesis by a computerized image analysis in MMM patients. Compared with five normal subjects, spleen CD34-staining capillary vascular density (CVD) was 2.1-3.03 times higher than the upper range of normal in six of the 15 (40%) MMM patients. CD8-staining sinusoidal vascular density (SVD) was constantly normal or lesser than normal and was inversely correlated with CVD (R = -0.53; P = 0.04). In MMM patients who did not receive cytoreductive or radiation therapy in the month before splenectomy (n = 9), the CVD was a significant determinant of spleen size (R = 0.88; P = 0.04). In MMM patients, the number of spleen CD34+ haematopoietic stem cells was increased from 1.2 to 98 times the upper limit of normal, and predicted the expansion of CVD (R = 0.57; P = 0.03). A population of cells expressing the CD34+/CD133+/VEGFR-2+ angiopoietic phenotype was present in the blood and spleen of five of seven patients. These results document that neoangiogenesis is an integral component of spleen re-localization of haematopoietic stem cells and suggest a cellular mechanism for spleen neoangiogenesis.     

Cytoreductive effect of recombinant alpha interferon in patients with myelofibrosis with myeloid metaplasia

Summary In an attempt to reduce myeloproliferation, we administered recombinant -2b interferon (r-INF) to ten patients with myelofibrosis with myeloid metaplasia (MMM) in a hypercellular phase, as part of a phase II trial. Two patients experienced severe side effects and stopped treatment before completion of the first week. In the eight evaluable patients, r-INF was given for 16 weeks at an initial dosage of 3×10⁶ U/day, with monthly increments in the case of response failure, i.e. a decrease in WBC or platelet count of less than 25% of the initial value. Two cases responded at the starting dosage, while the effective dosage was 5×10⁶ U/day in the others. At the end of the 16th week, Hb showed minor changes: from an initial value of 12.08 g/dl, range 8.3–17.3, to 11.6 g/dl, range 7.7–18 (P=0.12); WBC were reduced from 54×10⁹/l, range 6.4–69.4, to 17.5×10⁹/l, range 5–39 (P=0.09, 4/8 responses); platelets decreased from 775×10⁹/l, range 215–1748, to 403×10⁹/l, range 118–730 (P=0.008, 8/8 responses). Minor changes in spleen size were also noted, while no significant changes in bone marrow fibrosis occurred. Influenza-like symptoms and fatigue were common side effects. In conclusion, r-INF has a role as a non-leukemogenic cytoreductive agent in the therapy of MMM, especially for cases with thrombocytosis.     

Leukemogenic risk of hydroxyurea therapy in polycythemia vera,essential thrombocythemia,and myeloid metaplasia with myelofibrosis

In polycythemia vera (PV), treatment with chlorambucil and radioactive phosphorus (p32) increases the risk of leukemic transformation from 1% to 13–14%. This risk has been estimated to be 1–5.9% with hydroxyurea (HU) therapy. When compared with historical controls, the risk with use of HU does not appear to be statistically significant. The leukemogenic risk of HU therapy in essential thrombocytosis (ET) and in myelofibrosis with myeloid metaplasia (MMM) is unknown. HU remains the main myelotoxic agent in the treatment of PV, ET, and MMM. We studied 64 patients with these three disorders, seen at our institution during 1993–1995. The patients were studied for their clinical characteristics at diagnosis, therapies received, and development of myelodysplasia or acute leukemia (MDS/AL). Forty-two had PV, 15 ET, and 6 MMM, and 1 had an unclassified myeloproliferative disorder. Of the 42 patients with PV, 18 were treated with phlebotomy alone, 16 with HU alone, 2 with p32, 2 with multiple myelotoxic agents, and 2 with interferon-α(IFN-α). Two patients from the phlebotomy-treated group, one from the HU-treated group, and 1 from the multiple myelotoxic agent-treated group developed MDS/AL in the larger group, 11 received no treatment or aspirin alone, 18 were treated with phlebotomy alone, 25 with HU, 5 with multiple myelotoxic agents, 2 with p32, 2 with IFN-α, and 1 with melphalan. Study of the entire group of 64 patients showed that only one additional patient (total of 5 out of 64) developed MDS/AL. This patient had been treated with HU alone. Statistical analysis did not show any association between clinical characteristics at diagnosis, or HU therapy, and development of MDS/AL (P = 0.5). Thus, our data provide no evidence suggestive of increased risk of transformation to MDS/AL with HU therapy in PV, ET, and MMM. Larger, prospective studies are needed to study this issue further. © 1996 Wiley-Liss, Inc.     

Comparison of peripheral blood interphase cytogenetics with bone marrow karyotype analysis in myelofibrosis with myeloid metaplasia

In a prospective study of 42 patients with myelofibrosis with myeloid metaplasia (MMM), peripheral blood (PB) and bone marrow (BM) interphase cytogenetics and PB CD34 enumeration were performed concomitantly with BM karyotype analysis. Interphase cytogenetics was performed with a panel of fluorescence in situ hybridization (FISH) probes that were capable of detecting most of the known recurrent cytogenetic lesions in MMM. There was a close concordance in the results of interphase cytogenetics between PB and BM, regardless of the PB CD34 count. In general, FISH-detectable abnormalities were also detected by BM karyotype. Although complementary, interphase cytogenetics may not always provide the necessary karyotypic information in MMM.     

Bone marrow expression of vascular endothelial growth factor in myelofibrosis with myeloid metaplasia

The biologic relevance and prognostic impact of angiogenesis is being increasingly recognized in many solid tumors and hematologic malignancies including myelofibrosis with myeloid metaplasia (MMM). Many cytokines including vascular endothelial growth factor (VEGF) have been implicated for neoangiogenesis in MMM. However, the exact humoral basis remains to be elucidated. We examined the expression of VEGF by immunohistochemistry in a prospective cohort of 66 MMM patients, including six with cellular phase disease, and five normal controls. Contrary to most other hematologic malignancies, the distribution and intensity of staining for VEGF in bone marrow was similar between the MMM patients and controls. Interestingly, all six cellular phase patients displayed significantly increased VEGF expression. Thus, upregulation of angiogenic cytokines other than VEGF such as TGF-beta or loss of activity of an anti-angiogenic cytokine might be the dominant pathway of endothelial activation in MMM. However, VEGF might contribute to the process in the early stages of the disease.     

Lymphoblastic leukemic transformation (lymphoblastic crisis) in myelofibrosis and myeloid metaplasia

Acute lymphoblastic leukemia (ALL) developing in myelofibrosis (MF) and myeloid metaplasia (MM) is reported in two patients. In both cases, the clinical course of the "blastic crisis" was rapidly progressive with little response to chemotherapy. The circulating cells were readily identified as lymphoblasts on the basis of cytology, cytochemistry, immunologic studies, and ultrastructure. In one of the cases, 40% of cells had T-cell markers and all cells contained paranuclear acid phosphatase. In the second case, cells had a "Burkitt-like appearance, contained multiple cytoplasmic vacuoles positive for oil red O, and one-third of them had B-cell markers. The development of lymphoblastic crisis in MF and MM occurs rarely, is analogous to blastic transformation in chronic granulocytic leukemia, and supports the hypothesis that myeloproliferative disorders originate from pluripotent hematopoietic stem cells.