Postpolycythemic Myeloid Metaplasia Research Articles

The spleen microenvironment influences disease transformation in a mouse model of KITD816V-dependent myeloproliferative neoplasm

Activating mutations leading to ligand-independent signaling of the stem cell factor receptor KIT are associated with several hematopoietic malignancies. One of the most common alterations is the D816V mutation. In this study, we characterized mice, which conditionally express the humanized KITD816V receptor in the adult hematopoietic system to determine the pathological consequences of unrestrained KIT signaling during blood cell development. We found that KITD816V mutant animals acquired a myeloproliferative neoplasm similar to polycythemia vera, marked by a massive increase in red blood cells and severe splenomegaly caused by excessive extramedullary erythropoiesis. Moreover, we found mobilization of stem cells from bone marrow to the spleen. Splenectomy prior to KITD816V induction prevented expansion of red blood cells, but rapidly lead to a state of aplastic anemia and bone marrow fibrosis, reminiscent of post polycythemic myeloid metaplasia, the spent phase of polycythemia vera. Our results show that the extramedullary hematopoietic niche microenvironment significantly influences disease outcome in KITD816V mutant mice, turning this model a valuable tool for studying the interplay between functionally abnormal hematopoietic cells and their microenvironment during development of polycythemia vera-like disease and myelofibrosis.

Clinical Correlates of Serum Pro-Major Basic Protein in a Spectrum of Eosinophilic Disorders and Myelofibrosis

Background/Aims: Eosinophil cytoplasmic granules contain major basic protein (MBP), which is primarily translated from its precursor, proMBP. In this study, we evaluated the plasma level of proMBP in eosinophilic and chronic myeloproliferative disorders (MPN). Methods: The levels of plasma proMBP were measured by radioimmunoassay in 25 healthy controls, 23 patients with systemic mastocytosis (SM), 11 patients with idiopathic eosinophilia (IE) and a cohort of 170 patients with MPN which included 76 patients with de novo myelofibrosis, 42 with polycythemia vera (PV), 17 with postpolycythemic myeloid metaplasia (Post-PV MF), 21 with essential thrombocythemia (ET) and 14 with postthrombocythemic myeloid metaplasia (Post-ET MF). Results: The plasma proMBP level was significantly higher in patients with SM with eosinophilia (p < 0.001), IE (p < 0.001) and MPN with eosinophilia (p = 0.002) than in healthy controls. The median proMBP level of Post-PV MF and Post-ET MF patients was significantly higher than in PV and ET patients (p < 0.001 and p = 0.009, respectively). In IE patients, elevated proMBP was significantly correlated with the presence of splenomegaly (p < 0.05). In 76 de novo myelofibrosis patients, the proMBP level was correlated with spleen size and the presence of hypercatabolic symptoms. Conclusion: The significantly elevated levels of proMBP in myelofibrosis patients implies that proMBP could be an important stromal cytokine in bone marrow fibrosis.

Phenotypic Differences amongst Subgroups of Patients with Myelofibrosis with Myeloid Metaplasia (MMM): Analysis of 458 MMM Patients.

Background: Debate continues as to the clinical relevance of subclassifying patients with the myeloproliferative disorder (MPD) MMM into the subgroups of agnogenic myeloid metaplasia (AMM), post-polycythemic myeloid metaplasia (PPMM), and post-thrombocythemic myeloid metaplasia (PTMM). We looked to validate previously described phenotypic variability amongst subtypes, and explore relevant and differences in constitutional symptoms.Methods: An detailed analysis of patients with MMM whom responded to an international web based survey of MPD patients which registered responses regarding diagnosis, disease course, complete blood counts, co-morbidities (Charlson Co-morbidity index), symptoms, and fatigue (Fact-An and Brief Fatigue Inventory (BFI)).Results: A total of 456 patients self described as MMM responded of which 32.3% had AMM (n = 148), 38.0% % had PPMM (n = 174), and 29.7% had PTMM (n = 136). Detailed breakdown of differences in demographics, clinical course, current laboratory studies, treatment history, and current symptoms are outlined in the table below.Phenotypic Variability Amongst 458 MMM PatientsCategoryAMM (N=148; 32.3%)PPMM (N=174; 38.0%)PTMM (N=136; 29.7%)MMM Total (N=458)Δ between groups (p = )Age (Median)615757580.09Sex (% Males)60%49%30%47%<0.01Yrs from MPD Dx5686<0.01Labs/ Prior HistoryHb (g/dL)11.013.711.612.1<0.01% with RBC Tx43%6%11%20%<0.01Leukocytes (×10(9)/L)8.07.67.27.70.64Platelets (×10(9))/L)200352396321<0.01% with Splenomegaly76%49%41%54%<0.01% with Prior Thrombosis10%22%31%21%<0.01% with Prior Bleed16%20%31%22%0.01Treatment History for the MMM% with Prior Tx for MPD64%88%77%77%<0.01% Medical Therapy57%70%75%67%<0.01# Meds (Median (Range))1 (0–8)2 (0–6)2 (0–6)2 (0–8)<0.01% with Splenectomy8%5%6%6%0.48% with SCT6%1%1%3%<0.01MMM Associated Constitutional Symptoms% with Fatigue85%81%85%84%0.56% with Bone Pain51%46%44%47%0.51% with Fevers19%17%18%18%0.87% with Pruritus39%69%39%50%<0.01% with Night Sweats55%58%53%56%0.67% with Weight Loss30%15%16%20%<0.01Hb = Hemoglobin; SCT = Stem Cell TransplantOverall the data suggests patients with AMM are more likely male, with greater burdens of anemia, splenomegaly, and weight loss. However they are less likely to have experienced thrombohemorrhagic complications and have received fewer MPD medications. In contrast PPMM patients (not unsurprisingly) have little trouble from anemia, but have the most pruritus. Patients with PTMM are most likely female, with the highest platelet counts, and the greatest likelihood of thrombohemorrhagic complications. Additionally, all three subgroups of MMM had significant fatigue compared to published controls for both fatigue instruments (P<0.0001) yet there was no difference between MMM subtypes for the severity of fatigue.Conclusions: A large unselected series of MMM patients supports that although constitutional symptoms are significant and similar amongst MMM subgroups, these patients have variable burdens of other MPD manifestations.

Is it justified to perform a bone marrow biopsy examination in sustained erythrocytosis?

The diagnostic criteria of the Polycythemia Vera Study Group do not consider bone marrow histopathology, nor do they recognize the dynamics of polycythemia vera (PV). Precursor stages, when accompanied by an elevated platelet count, may clinically mimic essential thrombocythemia. Significantly extending former descriptions of bone marrow features, a trilineage myeloproliferation (panmyelosis) with a pleomorphous appearance (differences in size) of megakaryopoiesis is a characteristic histopathologic finding in PV. Differentiation from secondary polycythemia is accomplished by also considering the conspicuously expressed stromal changes (perivascular plasmacytosis, eosinophils, cell debris, and iron deposits). A clear-cut discrimination is possible, even in the initial (latent) stages of PV, which do not fulfill all the conventional diagnostic criteria. Advanced stages (spent phases) of PV show an increased left-shifted granulocytic proliferation accompanied by reduction of erythroid precursors and progressive myelofibrosis (postpolycythemic myeloid metaplasia). Finally, an increase in dysplastic changes and immaturity of cell lineages signals a transition into blastic crisis.

Molecular Progenitor Profiling in Human Myeloproliferative Disorders.

Myeloproliferative disorders (MPD) are clonal hematopoietic disorders characterized by a hypercellular marrow, an overabundance of distinct lineages of terminally differentiated progeny and a propensity to transform to acute myelogenous leukemia (AML). Recent reports revealed that a specific (V617F) mutation in JAK2 resulted in constitutive cytokine signaling and increased sensitivity to cytokines in a large proportion of patients with MPD. However, the stage of hematopoiesis at which this mutation occurs and whether additional mutations contribute to the evolution of MPD into AML has yet to be determined. We performed phenotypic and functional analyses of hematopoeitic stem cells (HSC), common myeloid progenitors (CMP), granulocyte-macrophage progenitors (GMP) and megakaryocyte-erythroid progenitors (MEP) in 63 MPD peripheral blood or bone marrow samples donated by patients with PV (n=15), essential thrombocythemia (ET; n=8), post-polycythemic myeloid metaplasia/myelofibrosis (PPMM/MF; n=5), chronic myelogenous leukemia (CML; n=7), atypical CML/myeloproliferative disease unspecified (aCML/UMPD; n=2), chronic eosinophilic leukemia (CEL; n=1), chronic myelomonocytic leukemia (CMML; n=13) and AML (n=12) in order to identify the stage of hematopoiesis at which mutations arose as well as to provide prognostic information on patients with a propensity to transform to AML. Of the MPD mononuclear cells sequenced, 12 of 15 PV, 2 of 5 ET, 3 of 3 post-polycythemic myeloid metaplasia, and 2 of 2 aCML samples were positive for the JAK2 V617F mutation. With regard to phenotypic changes in progenitor profiles, PV samples had an increase in CMP together with a distinctive IL-3Ra high population that distinguished it from all other MPD. Conversely, aCML, AML and proliferative CMML had a preponderance of GMP. Functional changes in progenitors were assessed using hematopoietic progenitor assays (Figure 1A and B). This methodology demonstrated that the differentiation potential of PV was already skewed toward the erythroid lineage at the HSC level in contrast to CMML, CML, aCML and AML HSC which produced a preponderance of myeloid colonies. In addition, the aberrant erythroid potential of PV HSC could be potently inhibited with a specific JAK2 inhibitor - AG490 suggesting that JAK2 plays a role in enhancing the erythroid differentiation potential of PV at the stem cell level. Finally, other molecular abnormalities were detected at the progenitor level in MPD including changes in GATA-1 and PU.1 expression, bcl-2 overexpression and beta-catenin activation that were associated with progression to AML. Thus, molecular progenitor profiling may provide prognostic information in a variety of MPD and could be a useful adjunct to current diagnostic methods. [Display omitted] [Display omitted]

Diagnostic impact of bone marrow histopathology in polycythemia vera (PV).

The criteria of the Polycythemia Vera Study Group (PVSG), although acknowledged as the gold standard to establish the diagnosis of polycythemia vera (PV), do not regard bone marrow (BM) histopathology. Arguments include the existence of sufficient objective markers of disease and the lack of independently performed morphological studies or standardized criteria. The aim of this review is to evaluate morphological characteristics of erythrocytosis and to determine whether distinctive patterns of histopathology exist. A review of the pertinent literature and evaluation of 334 patients from our files with a borderline to marked increase in hemoglobin was performed. In extension to former descriptions of BM features by the PVSG, a tri-lineage myeloproliferation (panmyelosis) with a pleomorphous appearance of megakaryopoiesis revealed that, besides increase in size, there was a lack of gross cytological anomalies. Differentiation from secondary polycythemia (SP) was accomplished by regarding these features and the conspicuously expressed stromal changes (plasmacytosis, eosinophils, cell debris and iron deposits). In about 96% of this cohort a clear-cut separation from SP was achieved, even in the initial (latent) stages. When accompanied by an elevated platelet count, these precursor stages may clinically mimick essential thrombocythemia because they are not recognized by the conventional criteria. Advanced stages (spent phases) of PV were consistent with an increased left-shifted granulocytic proliferation, accompanied by reduction of erythroid precursors and progressive myelofibrosis (post-polycythemic myeloid metaplasia). Finally, an increase in dysplastic changes and immaturity signalled a transition into blastic crisis. In conclusion, PV is characterized by a distinctive pattern of histopathology that has been gained in an independent and blind fashion and therefore, dissolves arguments about failing specificity.

Blood CD34 Count in Myelofibrosis with Myeloid Metaplasia: A Prospective Evaluation of Prognostic Value in 94 Patients.

Background: Previously established adverse prognostic factors in myelofibrosis with myeloid metaplasia (MMM) include anemia (hemoglobin < 10 g/dL), leukocytosis or leukopenia, presence of circulating blasts, and hypercatabolic symptoms (Dupriez et al. 1996;88:1013, Cervantes et al. BJH 1998; 102:684). Measurement of peripheral blood (PB) CD34 count has been shown to have diagnostic as well as possible prognostic value in MMM (Barosi et al. Blood 2001; 98:3249).Methods: A concurrent evaluation of PB CD34 count, bone marrow histology, and other clinical and laboratory parameters was conducted in a consecutive cohort of both newly and previously diagnosed patients with MMM. The study patients were prospectively followed for a minimum of 3 years in order to determine the prognostic value of PB CD34 count on survival, leukemic transformation, and disease progression from the time of PB CD34 analysis.Results:i. Patient cohort: A total of 94 patients (median age 61 years, range 26–81; 61 males) were accrued between January 2000 and August 2001 and subsequently followed through July 2004. MMM subtypes included agnogenic myeloid metaplasia (AMM; 58 patients), post-polycythemic myeloid metaplasia (PPMM; 12 patients), post-thrombocythemic myeloid metaplasia (PTMM; 12 patients), cellular phase MMM (8 patients) and hypocellular variant MMM (4 patients). At the time of study entry, 19 patients (20%) were newly diagnosed and 75 were established cases (median of 36 months from initial diagnosis, range 4–221). The Dupriez prognostic scores were 0 in 37 (39%), 1 in 37 (39%), and 2 in 20 patients (21%).ii) Clinical correlates of PB CD34 count: The median PB CD34 count for the entire study cohort was 54.7 x 106/L (range 0–5345) with 85% patients having increased values (> 5 x 106/L). Cellular phase MMM and PPMM had significantly lower PB CD34 counts compared to the other MMM subtypes. On univariate analysis, PB CD34 count significantly correlated with Dupriez prognostic score, leukocyte count, circulating blast or immature myeloid cell percentage, and presence of hypercatabolic symptoms but not with age, gender, anemia (hemoglobin < 10 g/dL), abnormal cytogenetics, disease duration, treatment history, splenectomy status, nucleated RBC count (NRBC), platelet count, or bone marrow histology including fibrosis, osteosclerosis, and angiogenesis. On multivariate analysis, only leukocyte count and PB blast or immature myeloid cell percentage retained their significance.iii) Prognostic evaluation of PB CD34 count: As of July 16, 2004, 43 patients (46%) have died and median duration of follow up in the surviving patients was 41 months (range 36–54). The projected overall survival at 5 years was 50%. On Cox proportional regression analysis, individual variables that correlated with inferior survival included anemia (hemoglobin < 10 g/dL), advanced age, presence of hypercatabolic symptoms, abnormal cytogenetics, and increased leukocyte count, circulating blast percentage, Dupriez prognostic score, and NRBC. PB CD34 count displayed borderline significance (p=0.06). However, on multivariate analysis, only anemia, leukocytosis, and age retained prognostic significance. Similarly, PB CD34 count did not predict either subsequent leukemic transformation or disease progression.Conclusion: PB CD34 count is often but not always increased in MMM and correlates significantly with leukocytosis and degree of PB myeloid immaturity. The current prospective study does not support an independent prognostic value for PB CD34 count in MMM.

Outcome of allogeneic stem cell transplantation in patients with myelofibrosis.

Myelofibrosis, either de novo or following pre-existing hematologic diseases, can be cured by allogeneic hematopoietic stem cell transplantation (SCT), but SCT is associated with significant morbidity and mortality, making the choice and timing of transplantation difficult. In all, 20 patients (seven female and 13 male), with a median age of 45 years (range 22-57 years), with idiopathic myelofibrosis (n = 12), post-thrombocythemic (n = 3) or post-polycythemic (n = 2) myeloid metaplasia or leukemic transformation (n = 3), underwent allogeneic SCT at our center between 1994 and 2003. With regard to the pre-transplant presence of risk factors such as hemoglobin levels < or =10 mg/dl, grade III marrow fibrosis or peripheral blast counts >1%, patients were divided into high- and low-risk groups. The estimated 3-year survival post transplant was 38.5% for all patients. The 3-year probability of survival within the high-risk group (n = 11) characterized by the presence of at least two risk factors was 16%. Low-risk patients (n = 9) with at most one risk factor had an estimated 3-year survival of 67%. Thus, previously defined risk determinants for the outcome of allogeneic transplantation for myelofibrosis may provide useful information facilitating treatment strategies. Our data suggest that transplantation should be taken into consideration before poor prognostic variables develop.

Therapeutic options for essential thrombocythemia and polycythemia vera.

Several options exist for treating essential thrombocythemia and polycythemia vera. One approach is to assign the patient to a risk category from which treatment recommendations follow. The principal risks of essential thrombocythemia include thrombosis, major hemorrhage, and conversion to leukemia or myelofibrosis. Risk factors for thrombosis include age and prior thrombosis. Smoking and obesity have been implicated in isolated series. High-risk patients with essential thrombocythemia can be defined as those 60 years of age or older or those who have had a thrombosis at any age. These patients should be treated with hydroxyurea. If hydroxyurea cannot be tolerated, anagrelide and interferon-alpha (IFN-alpha) are alternatives. Low-dose aspirin (40 to 325 mg) can be used for patients whose platelet counts are < 1,500 x10(9)/L. Low-risk patients are those less than 60 years old who have not had thrombosis, who have no cardiovascular risk factors, and whose platelet counts are < 1,500 x 10(9)/L. These patients can be observed or placed on low-dose aspirin. Intermediate-risk patients are those less than 60 years who have not had thromboses, but who have platelet counts > 1,500 x 10(9)/L or who have significant cardiovascular risk factors. These patients should have their risk factors treated and may be given low-dose aspirin if the platelet count is < 1,500 x 10(9)/L. They can be observed or treated with anagrelide, hydroxyurea, or IFN-alpha. The Mayo Clinic experience suggests that no specific treatment affects outcomes of pregnancies. In high-risk pregnant women who need treatment, IFN-alpha is used. The principal risks of polycythemia vera are thrombosis, postpolycythemia myeloid metaplasia, and acute leukemia. Risk factors for thrombosis include age, the use of phlebotomies, the rate of phlebotomies, and a prior history of thrombosis. Platelet counts have not been definitively linked to an increased risk of thrombosis. High-risk polycythemia vera patients are those 60 years of age or older (some groups use 70 years) or those of any age who have had thrombosis. They should be treated with phlebotomy and hydroxyurea or IFN-alpha. Selected patients may be treated with anagrelide. A typical target range for phlebotomy is a hematocrit of < 42% for women and < 45% for men. Low-dose aspirin can be used if the platelet count is < 1,500 x 10(9)/L. Low-risk patients are those less than 60 years old who have had no thrombosis, no cardiovascular risk factors, and whose platelets are < 1,500 x 10(9)/L. These patients can be managed with phlebotomy alone or phlebotomy and low-dose aspirin. Intermediate-risk patients are those who are less than 60 years old, who have not had thrombosis, but who have platelet counts > 1,500 x 10(9)/L or who have cardiovascular risk factors. The cardiovascular risk factors should be treated, along with phlebotomy alone or with IFN-alpha. Low-dose aspirin is reasonable for those with platelet counts < 1,500 x 10(9)/mL. Anagrelide can be used with phlebotomy in selected patients. Women of childbearing age who are in the low-risk or intermediate-risk group can be treated with phlebotomy alone and low-dose aspirin if the platelet count is < 1,500 x 10(9)/L. For high-risk patients or pregnant patients, IFN-alpha can be added.

Therapeutic options for essential thrombocythemia and polycythemia vera

Several options exist for treating essential thrombocythemia and polycythemia vera. One approach is to assign the patient to a risk category from which treatment recommendations follow. The principal risks of essential thrombocythemia include thrombosis, major hemorrhage, and conversion to leukemia or myelofibrosis. Risk factors for thrombosis include age and prior thrombosis. Smoking and obesity have been implicated in isolated series. High-risk patients with essential thrombocythemia can be defined as those 60 years of age or older or those who have had a thrombosis at any age. These patients should be treated with hydroxyurea. If hydroxyurea cannot be tolerated, anagrelide and interferon-alpha (IFN-α) are alternatives. Low-dose aspirin (40 to 325 mg) can be used for patients whose platelet counts are < 1,500 ×10 9/L. Low-risk patients are those less than 60 years old who have not had thrombosis, who have no cardiovascular risk factors, and whose platelet counts are < 1,500 × 10 9/L. These patients can be observed or placed on low-dose aspirin. Intermediate-risk patients are those less than 60 years who have not had thromboses, but who have platelet counts > 1,500 × 10 9/L or who have significant cardiovascular risk factors. These patients should have their risk factors treated and may be given low-dose aspirin if the platelet count is < 1,500 × 10 9/L. They can be observed or treated with anagrelide, hydroxyurea, or IFN-α. The Mayo Clinic experience suggests that no specific treatment affects outcomes of pregnancies. In high-risk pregnant women who need treatment, IFN-α is used. The principal risks of polycythemia vera are thrombosis, postpolycythemia myeloid metaplasia, and acute leukemia. Risk factors for thrombosis include age, the use of phlebotomies, the rate of phlebotomies, and a prior history of thrombosis. Platelet counts have not been definitively linked to an increased risk of thrombosis. High-risk polycythemia vera patients are those 60 years of age or older (some groups use 70 years) or those of any age who have had thrombosis. They should be treated with phlebotomy and hydroxyurea or IFN-α. Selected patients may be treated with anagrelide. A typical target range for phlebotomy is a hematocrit of < 42% for women and < 45% for men. Low-dose aspirin can be used if the platelet count is < 1,500 × 10 9/L. Low-risk patients are those less than 60 years old who have had no thrombosis, no cardiovascular risk factors, and whose platelets are < 1,500 × 10 9/L. These patients can be managed with phlebotomy alone or phlebotomy and low-dose aspirin. Intermediate-risk patients are those who are less than 60 years old, who have not had thrombosis, but who have platelet counts > 1,500 × 10 9/L or who have cardiovascular risk factors. The cardiovascular risk factors should be treated, along with phlebotomy alone or with IFN-α. Low-dose aspirin is reasonable for those with platelet counts < 1,500 × 10 9/mL. Anagrelide can be used with phlebotomy in selected patients. Women of childbearing age who are in the low-risk or intermediate-risk group can be treated with phlebotomy alone and low-dose aspirin if the platelet count is < 1,500 × 10 9/L. For high-risk patients or pregnant patients, IFN-α can be added. Semin Oncol 29 (suppl 10):10-15. Copyright 2002, Elsevier Science (USA). All rights reserved.

Concomitant Primary Polycythemia Vera and Follicle Center Cell Non-Hodgkin Lymphoma: A Case Report and Review of the Literature

The association of myeloproliferative and lymphoproliferative disorders is well known after cytotoxic drug or radiation exposure, while it is remarkably rare prior to therapy. We report on a patient simultaneously diagnosed as having polycythemia vera and II 3 A follicle center cell non-Hodgkin lymphoma (grade 1). At this timepoint, he is on 12-year follow-up, characterized by post-polycythemia myeloid metaplasia with myelofibrosis and persistent complete remission of lymphoma. The conventional marrow cytogenetic analysis performed during the course of the disease demonstrated an abnormal karyotype with deletion of the long arm of chromosome 20 and trisomy 8, while molecular analysis failed to detect BCR-ABL rearrangement in peripheral blood cells. To the best of our knowledge based on a computer-aided review of the literature (MED-LINE 1966-2002), this is the sixth case of concomitant primary polycythemia vera and lymphoma of non-Hodgkin type. Besides, there is a single literature report on polycythemia vera coexisting with the Hodgkin's lymphoma. In our case as well as in the recorded ones, two independent malignant clones of myeloid and lymphoid origin, respectively, seem to have arisen. Further reports, supported by chromosomal and molecular studies, could improve our knowledge on this extremely infrequent disease association.

Risk of the Hemolytic–Uremic Syndrome after Antibiotic Treatment ofEscherichia coliO157:H7 Infections

C ORR ES POND ENCE 1. Tefferi A. Myelofibrosis with myeloid metaplasia. N Engl J Med 2000; Risk of the Hemolytic–Uremic Syndrome after Antibiotic Treatment of Escherichia coli O157:H7 Infections To the Editor: Wong et al. (June 29 issue) 1 report an as- sociation between antibiotic treatment in children with acute diarrhea caused by Escherichia coli O157:H7 and the devel- opment of the hemolytic–uremic syndrome. In Chile, shi- gella species cause 30 percent of cases of bloody diarrhea in children and enterohemorrhagic strains of E. coli cause 37 percent of such cases 2 — a situation that may also be com- mon in developing countries. For children with acute bloody diarrhea in these countries, the most widely accepted rec- ommendation is to obtain a stool culture and initiate empir- ical antibiotic treatment for shigella, because appropriate treatment shortens the duration of the diarrhea, decreases the incidence of complications, and reduces the risk of trans- mission by shortening the duration of bacterial shedding. 3 Given these points, the results presented by Wong et al. raise several questions. Knowing that E. coli O157:H7 and shigella species cannot be differentiated early in the clinical course on the basis of clinical findings or simple laboratory tests, does the potentially increased risk of the hemolytic– uremic syndrome associated with empirical antibiotic treat- ment of E. coli O157:H7 infections outweigh the risk of not treating shigella infections during the 72 hours need- ed to obtain culture results? In Chile, 70 percent of cases of the hemolytic–uremic syndrome are associated with se- rotypes of E. coli other than O157:H7. 4 Can the increased risk of the hemolytic–uremic syndrome in children who receive antibiotics for E. coli O157:H7 infections be extrap- olated to other strains of the organism? We worry that the message of this study will be extended prematurely to the treatment of bloody diarrhea worldwide. In places where the prevalence of shigella and E. coli infec- tions is similar and strains of E. coli other than O157:H7 are common, withholding antibiotic therapy until the cause of the diarrhea is known may have more risks than benefits. A M IGUEL O’R YAN , M.D. V ALERIA P RADO , M.D. University of Chile Santiago, Chile B Figure 1. Lesions of the Skin (Panel A) and Mouth (Panel B) in a Patient with Post-Polycythemic Myeloid Metaplasia. serious exacerbation of post-polycythemic myeloid metapla- sia in a patient who was receiving epoetin may be uncom- mon, but it is striking and should be recognized as a poten- tial sequela of such treatment. A BDUL R AHMAN J AZIEH , M.D., M.P.H. University of Cincinnati Cincinnati, OH 45267 1. Wong C, Jelacic S, Habeeb RL, Watkins SL, Tarr PI. The risk of the hemolytic–uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med 2000;342:1930-6. 2. Lopez EL, Prado-Jimenez V, O’Ryan-Gallardo M, Contrini MM. Shi- gella and Shiga toxin-producing Escherichia coli causing bloody diarrhea in Latin America. Infect Dis Clin North Am 2000;14:41-65, viii. 3. Haltalin KC, Nelson JD, Ring R III, Sladoje M, Hinton LV. Double- blind treatment study of shigellosis comparing ampicillin, sulfadiazine, and placebo. J Pediatr 1967;70:970-81. 4. Prado JV, Martinez DJ, Arellano CC, Levine MM. Variacion temporal de genotipos y serogrupos de E Coli enterohemorragicos aislados en ninos chilenos con infecciones intestinales o sindrome hemolitico-uremico. Rev Med Chil 1997;125:291-7. M OHAMMAD J. K YASA , M.D. University of Arkansas for Medical Sciences Little Rock, AR 72205 To the Editor: We question some of the epidemiologic concepts and analyses used by Wong et al. They justified the Vol ume 343 The New England Journal of Medicine Downloaded from nejm.org at Berkeley (UCB) on February 19, 2017. For personal use only. No other uses without permission. Copyright © 2000 Massachusetts Medical Society. All rights reserved. Numb e r 17

A Patient with Myeloid Metaplasia of the Skin and Mouth

To the Editor: Post-polycythemic myeloid metaplasia is characterized by increasing splenomegaly, dacryocytes, anemia, extensive bone marrow fibrosis, and a leukoerythroblastic blood picture.1 We de...

Polycythemia vera in Chinese patients: thirty-six years of experience.

Forty-one patients with polycythemia vera (PV) according to the PVSG criteria were analysed retrospectively from January 1960 to March 1996. There were 23 male and 18 female patients with a median follow-up of 66.5 months (3-431 months). Median age was 62 (range: 37-85). The median hemoglobin level at diagnosis was 18.8 g/dl. Four patients were treated by venesection alone, 20 patients received hydroxyurea and intermittent venesection, 3 were treated with radioactive phosphorus alone, and 14 had both hydroxyurea and radioactive phosphorus. During the course of illness, 14 patients (34%) developed a total of 19 thrombotic events. Of the thrombotic events, 16 were arterial and 3 were venous. Two patients had both arterial and venous thrombosis sequentially. The probability of thrombosis-free survival after treatment was 83% at 10 years and 73% at 20 years. One patient developed post-polycythemic myeloid metaplasia 24 months after diagnosis. Of 17 patients exposed to radioactive phosphorus, only 1 developed secondary acute myeloid leukemia (AML) 9 years afterwards. Of the 20 patients treated with hydroxyurea for a median duration of 63.5 months (2-130 months), there is no case of secondary malignancy. Overall survival was 83% at 10 years and 62% at 20 years. In conclusion, PV in Chinese is a relatively benign disease with a low risk of thrombosis as compared to Caucasian patients. Hydroxyurea has a very low risk of secondary leukemia and is a safe drug to use in Chinese patients with PV.

Polycythemia vera.

Polycythemia vera (PV) is one of the myeloproliferative diseases, and, as such, is an example of clonal hematopoiesis. The progeny of a single, abnormal, hematopoietic stem cell gain a growth advantage over their normal counterparts resulting in overproduction of red cells generally accompanied by overproduction of granulocytes and platelets as well. There are a variety of nonspecific symptoms at onset related to the increased red cell mass and hematocrit accompanied by the more specific manifestations of pruritus, erythromelalgia, and hepatic, portal, and mesenteric vein thrombosis. Splenomegaly and hypertension are common. The laboratory hallmark is an increased red cell mass. There is also often an increase in white cell count, platelet count, and leukocyte alkaline phosphatase along with other findings reflecting the increased rate of turnover of hematopoietic cells. The bone marrow biopsy generally displays hypercellularity involving all three cell lines and absent iron stores. The diagnosis of PV depends on excluding spurious polycythemia in which there is a high hematocrit but a normal red cell mass and secondary polycythemia in which there is an increased red cell mass in response to tissue hypoxia or the inappropriate production of erythropoietin, generally by a tumor. In addition, one should try to establish the diagnosis in a positive fashion by a combination of studies of the blood and bone marrow. Phlebotomy and occasionally plateletpheresis should be used as acute therapy. Chronic therapy is guided by the knowledge that patients treated with phlebotomy alone have an increased rate of thrombotic complications particularly in older patients and those with previous thrombotic disease. Myelosuppressive therapy can reduce the incidence of these complications, but is commonly associated with an increased incidence of second malignancies, particularly acute leukemia. At present, hydroxyurea is the myelosuppressive agent of choice. Antiplatelet agents have a limited role except in the palliation of the syndrome of erythromelalgia. Median survival is approximately 10 years. As implied above, the causes of morbidity and mortality vary with the mode of chronic therapy which has been employed, leukemia being more common after myelosuppressive therapy and thrombotic complications being more common after therapy with phlebotomy alone. Ten percent to 50% of patients move into a spent phase followed by postpolycythemic myeloid metaplasia, irrespective of previous therapy employed. Eventually, the major problems may be cytopenias and massive splenomegaly.

Splenectomy in Agnogenic Myeloid Metaplasia and Postpolycythemic Myeloid Metaplasia

A retrospective analysis of 34 successive splenectomies in 137 patients with myelofibrosis was carried out. Indications, complications, and response to splenectomy were compared between 22 patients with agnogenic myeloid metaplasia (AMM) and 12 patients with postpolycythemic myeloid metaplasia (PPMM). Painful splenomegaly, refractory hemolytic anemia, and refractory thrombocytopenia were the common indications for surgery. The best results were obtained for painful splenomegaly. For the other indications, half to three fourths of the patients improved with splenectomy. An increased incidence of excessive hemorrhage, infected hematoma, and early mortality was more common in the PPMM group and was found to be connected with large spleens, prolonged bleeding time, and prominent thrombocytopenia. Persistent thrombocytosis after surgery was more common in the AMM group. Leukemic transformation seemed to be related to thrombocytosis and to prior therapy with alkylating agents. Median survival following splenectomy was 43 months in the AMM group and 32 months in the PPMM group. We conclude that splenectomy has a role in improving the quality of life by ameliorating mechanical discomfort and decreasing transfusion requirement in the late phase of AMM. However, in patients with PPMM, because of the high complication rate, splenectomy should be carefully considered for specific indications on an individual basis.

Splenectomy in agnogenic myeloid metaplasia and postpolycythemic myeloid metaplasia. A study of 34 cases

Splenectomy in agnogenic myeloid metaplasia and postpolycythemic myeloid metaplasia. A study of 34 cases

Small Intestinal Myeloid Metaplasia

Extramedullary hematopoiesis is rarely found in the gastrointestinal tract. A patient with postpolycythemic myeloid metaplasia who previously underwent splenectomy presented with recurrent, protracted gastrointestinal tract hemorrhage. Elaborate workup failed to reveal the source of bleeding. Intraoperative endoscopy with transillumination disclosed multiple submucosal lesions along the entire small bowel, which proved to be extramedullary hematopoiesis. After institution of hydroxyurea therapy, the rate of bleeding diminished considerably.

Splenic hematopoiesis in polycythemia vera. A morphologic and immunohistologic study.

Spleens from 42 patients with polycythemia vera were studied with immunohistologic technics to assess the degree of hematopoietic cellularity in an attempt to clarify the pathogenesis of the splenomegaly characteristic of this disorder. The 22 spleens obtained in the erythrocytotic phase showed striking congestion with mature erythrocytes but no significant extramedullary hematopoiesis. However, the 20 spleens obtained in the spent phase showed prominent trilinear extramedullary hematopoiesis. Increasing splenomegaly with extramedullary hematopoiesis correlated with the development of increased medullary reticulin and peripheral blood leukoerythroblastosis. Splenic myeloid metaplasia is not a feature of uncomplicated polycythemia vera, and its presence indicates progression to the spent phase, or postpolycythemic myeloid metaplasia. The authors' findings indicate that the presence of hematopoietic precursors in the spleen in the spent phase of polycythemia vera and in agnogenic myeloid metaplasia is a result of their filtration from the peripheral blood.

Postpolycythemic myeloid metaplasia, Sweet's syndrome, and acute myeloid leukemia

A 60-year-old man with postpolycythemic myeloid metaplasia developed acute neutrophilic dermatosis (Sweet's syndrome), which responded to systemic steroid therapy. Six months later he developed acute myelogenous blast crisis refractory to leukemic induction therapy.