Non-hepatosplenic Extramedullary Hematopoiesis Research Articles

Primary myelofibrosis: 2021 update on diagnosis, risk-stratification and management.

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell-derived clonal myeloproliferation that is often but not always accompanied by JAK2, CALR, or MPL mutations. Additional disease features include bone marrow reticulin/collagen fibrosis, aberrant inflammatory cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival. Bone marrow morphology is the primary basis for diagnosis. Presence of JAK2, CALR, or MPL mutation, expected in around 90% of the patients, is supportive but not essential for diagnosis; these mutations are also prevalent in the closely related MPNs, namely polycythemia vera (PV) and essential thrombocythemia (ET). The 2016 World Health Organization classification system distinguishes "prefibrotic" from "overtly fibrotic" PMF; the former might mimic ET in its presentation. Furthermore, approximately 15% of patients with ET or PV might progress into a PMF-like phenotype (post-ET/PV MF) during their clinical course. SRSF2, ASXL1, and U2AF1-Q157 mutations predict inferior survival in PMF, independent of each other and other risk factors. RAS/CBL mutations predicted resistance to ruxolitinib therapy. Very high risk abnormalities include -7, inv (3), i(17q), +21, +19, 12p-, and 11q-. Two new prognostic systems for PMF have recently been introduced: GIPSS (genetically-inspired prognostic scoring system) and MIPSS70+ version 2.0 (MIPSSv2; mutation- and karyotype-enhanced international prognostic scoring system). GIPSS is based exclusively on mutations and karyotype. MIPSSv2 includes, in addition, clinical risk factors. GIPSS features four and MIPSSv2 five risk categories. Observation alone is advised for MIPSSv2 "low" and "very low" risk disease (estimated 10-year survival 56%-92%); allogeneic hematopoietic stem cell transplant (AHSCT) is the preferred treatment for "very high" and "high" risk disease (estimated 10-year survival 0%-13%); treatment-requiring patients with intermediate-risk disease (estimated 10-year survival 30%) are best served by participating in clinical trials. In non-transplant candidates, conventional treatment for anemia includes androgens, prednisone, thalidomide, and danazol; for symptomatic splenomegaly, hydroxyurea and ruxolitinib; and for constitutional symptoms, ruxolitinib. Fedratinib, another JAK2 inhibitor, has now been FDA-approved for use in ruxolitinib failures. Splenectomy is considered for drug-refractory splenomegaly and involved field radiotherapy for non-hepatosplenic EMH and extremity bone pain. A number of new agents, alone or in combination with ruxolitinib, are currently under investigation for MF treatment (ClinicalTrials.gov); preliminary results from some of these clinical trials were presented at the 2020 ASH annual meeting and highlighted in the current document.

Primary myelofibrosis: 2019 update on diagnosis, risk-stratification and management.

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell-derived clonal myeloproliferation that is often but not always accompanied by JAK2, CALR, or MPL mutations; additional disease features include bone marrow stromal reaction including reticulin fibrosis, abnormal cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival. Diagnosis of PMF is based on bone marrow morphology. Presence of JAK2, CALR, or MPL mutation, expected in ∼ 90% of the patients, is supportive but not essential for diagnosis. The revised 2016 World Health Organization (WHO) classification system distinguishes "prefibrotic" from "overtly fibrotic" PMF; the former might mimic ET in its presentation and it is prognostically relevant to distinguish the two. Two new prognostic systems for PMF have recently been introduced: GIPSS (genetically inspired prognostic scoring system) and MIPSS70+ version 2.0 (mutation- and karyotype-enhanced international prognostic scoring system). GIPSS is based exclusively on mutations and karyotype. MIPSS70+ version 2.0 utilizes both genetic and clinical risk factors. GIPSS features four and MIPSS70+ version 2.0 five risk categories. MIPSS70+ version 2.0 requires an online score calculator (http://www.mipss70score.it) while GIPPS offers a lower complexity prognostic tool. Observation alone is advised for MIPSS70+ version 2.0 "low" and "very low" risk disease (estimated 10-year survival 56%-92%); allogeneic stem cell transplant is the preferred treatment of choice for "very high" and "high" risk disease (estimated 10-year survival 0-13%); treatment-requiring patients with intermediate-risk disease (estimated 10-year survival 30%) are best served by participating in clinical trials. All other treatment approaches, including the use of JAK2 inhibitors, are mostly palliative and should not be used in the absence of clear treatment indications. Conventional treatment for anemia includes androgens, prednisone, thalidomide and danazol, for symptomatic splenomegaly hydroxyurea and ruxolitinib and for constitutional symptoms ruxolitinib. Splenectomy is considered for drug-refractory splenomegaly and involved field radiotherapy for nonhepatosplenic EMH and extremity bone pain.

Primary myelofibrosis: 2017 update on diagnosis, risk-stratification, and management.

Diagnosis is based on bone marrow morphology. The presence of JAK2, CALR or MPL mutation is supportive but not essential for diagnosis; approximately 90% of patients carry one of these mutations and 10% are "triple-negative." None of these mutations are specific to PMF and are also seen in essential thrombocythemia (ET). According to the revised 2016 World Health Organization (WHO) classification and diagnostic criteria, "prefibrotic" PMF (pre-PMF) is distinguished from "overtly fibrotic" PMF; the former might mimic ET in its presentation and it is prognostically relevant to distinguish the two. Risk stratification: The Dynamic International Prognostic Scoring System-plus (DIPSS-plus) uses eight predictors of inferior survival: age >65 years, hemoglobin <10 g/dL, leukocytes >25 × 109 /L, circulating blasts ≥1%, constitutional symptoms, red cell transfusion dependency, platelet count <100 × 109 /L and unfavorable karyotype (i.e., complex karyotype or sole or two abnormalities that include +8, -7/7q-, i(17q), inv(3), 5/5q-, 12p-, or 11q23 rearrangement). The presence of 0, 1, "2 or 3" and ≥4 adverse factors defines low, intermediate-1, intermediate-2 and high-risk disease with median survivals of approximately 15.4, 6.5, 2.9 and 1.3 years, respectively. Most recently, DIPSS-plus-independent adverse prognostic relevance has been demonstrated for certain mutations including ASXL1 and SRSF2 whereas patients with type 1/like CALR mutations, compared to their counterparts with other driver mutations, displayed significantly better survival. Risk-adapted therapy: Observation alone is a reasonable treatment strategy for asymptomatic low or intermediate-1 DIPSS-plus risk disease, especially in the absence of high-risk mutations. All other patients with high or intermediate-2 risk disease, or those harboring high-risk mutations such as ASXL1 or SRSF2, should be considered for stem cell transplant, which is currently the only treatment modality with the potential to favorably modify the natural history of the disease. Non-transplant candidates should be encouraged to participate in clinical trials, since the value of conventional drug therapy, including the use of JAK2 inhibitors, is limited to symptoms palliation and reduction in spleen size. Specifically, JAK2 inhibitors have not been shown to induce complete clinical or cytogenetic remissions or significantly affect JAK2/CALR/MPL mutant allele burden. Splenectomy is considered for drug-refractory splenomegaly. Involved field radiotherapy is most useful for post-splenectomy hepatomegaly, non-hepatosplenic EMH, PMF-associated pulmonary hypertension and extremity bone pain. Am. J. Hematol. 91:1262-1271, 2016. © 2016 Wiley Periodicals, Inc.

Palliative Radiotherapy for Spinal Extramedullary Hematopoiesis in Thalassemia Major

Introduction: Non - hepatosplenic Extramedullary Hematopoiesis (NHEMH) is seen as a compensation mechanism in the patients with hematologic dysfunction. Thalassemia is an autosomal recessive hematologic disorder. The tissue involvement is seen very rarely in thalasemia major. Case: A 45 - years old patien t diagnosed with thalassemia major was presented in this case report. The patient had splenectomy after 12 years from diagnosis and he was followed with continuous blood transfusions. Due to the newly emerged chest pain and dyspnea, he was evaluated with c omputed tomography. The operation was done for paraspinal masses caused by NHEMH. But same complaints were seen after 5 years from the operation. Paraspinal and sacral recurrences Mini - r eview Article

Primary myelofibrosis: 2014 update on diagnosis, risk-stratification, and management.

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by stem cell-derived clonal myeloproliferation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival. DIAGNOSIS is based on bone marrow morphology. The presence of JAK2, CALR, or MPL mutation is supportive but not essential for diagnosis; approximately 90% of patients carry one of these mutations and 10% are "triple-negative." None of these mutations are specific to PMF and are also seen in essential thrombocythemia (ET). Prefibrotic PMF mimics ET in its presentation and the distinction, enabled by careful bone marrow morphological examination, is prognostically relevant. Differential diagnosis also includes chronic myeloid leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. The Dynamic International Prognostic Scoring System-plus (DIPSS-plus) uses eight predictors of inferior survival: age >65 years, hemoglobin <10 g/dL, leukocytes >25 × 10(9) /L, circulating blasts ≥1%, constitutional symptoms, red cell transfusion dependency, platelet count <100 × 10(9) /L, and unfavorable karyotype (i.e., complex karyotype or sole or two abnormalities that include +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p-, or 11q23 rearrangement). The presence of 0, 1, "2 or 3," and ≥4 adverse factors defines low, intermediate-1, intermediate-2, and high-risk disease with median survivals of approximately 15.4, 6.5, 2.9, and 1.3 years, respectively. High risk disease is also defined by CALR(-) /ASXL1(+) mutational status. Observation alone is adequate for asymptomatic low/intermediate-1 risk disease, especially with CALR(+) /ASXL1(-) mutational status. Stem cell transplant is considered for DIPSS-plus high risk disease or any risk disease with CALR(-) /ASXL1(+) mutational status. Investigational drug therapy is reasonable for symptomatic intermediate-1 or intermediate-2 risk disease. Splenectomy is considered for drug-refractory splenomegaly. Involved field radiotherapy is most useful for post-splenectomy hepatomegaly, non-hepatosplenic EMH, PMF-associated pulmonary hypertension, and extremity bone pain.

Primary myelofibrosis: 2013 update on diagnosis, risk‐stratification, and management

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by stem cell-derived clonal myeloproliferation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival. Diagnosis is based on bone marrow morphology. The presence of fibrosis, JAK2/MPL mutation, or +9/13q- cytogenetic abnormality is supportive but not essential for diagnosis. Prefibrotic PMF mimics essential thrombocythemia in its presentation and the distinction is prognostically relevant. Differential diagnosis of myelofibrosis should include chronic myeloid leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. The Dynamic International Prognostic Scoring System-plus (DIPSS-plus) prognostic model for PMF can be applied at any point during the disease course and uses eight independent predictors of inferior survival: age >65 years, hemoglobin <10 g/dL, leukocytes >25 × 10⁹/L, circulating blasts ≥ 1%, constitutional symptoms, red cell transfusion dependency, platelet count <100 × 10⁹/L, and unfavorable karyotype (i.e., complex karyotype or sole or two abnormalities that include +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p-, or 11q23 rearrangement). The presence of 0, 1, "2 or 3," and ≥ 4 adverse factors defines low, intermediate-1, intermediate-2, and high-risk disease with median survivals of approximately 15.4, 6.5, 2.9, and 1.3 years, respectively. A >80% two-year mortality is predicted by monosomal karyotype, inv(3)/i(17q) abnormalities, or any two of circulating blasts >9%, leukocytes ≥ 40 × 10⁹/L or other unfavorable karyotype. Most recently, mutations involving ASXL1, SRSF2, EZH2, and IDH1/2 or increased plasma IL-2R, IL-8, or serum-free light chain levels have been shown to adversely affect survival. Observation alone is adequate for asymptomatic low/intermediate-1 risk disease. Allogeneic stem cell transplantation (ASCT) is often considered for high risk disease. Conventional or experimental drug therapy is reasonable for symptomatic intermediate-1 or intermediate-2 risk disease; however, ASCT is an acceptable treatment option for such patients in the presence of ASXL1 or other prognostically adverse mutations. Splenectomy and low-dose radiotherapy are used for drug-refractory splenomegaly. Radiotherapy is also used for the treatment of non-hepatosplenic EMH, PMF-associated pulmonary hypertension, and extremity bone pain.

Primary myelofibrosis: 2012 update on diagnosis, risk stratification, and management

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by stem cell-derived clonal myeloproliferation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival. Diagnosis is based on bone marrow morphology. The presence of fibrosis, JAK2/MPL mutation or +9/13q- cytogenetic abnormality is supportive but not essential for diagnosis. Prefibrotic PMF mimics essential thrombocythemia in its presentation and the distinction is prognostically relevant. Differential diagnosis of myelofibrosis should include chronic myelogenous leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. The Dynamic International Prognostic Scoring System-plus (DIPSS-plus) prognostic model for PMF can be applied at any point during the disease course and uses eight independent predictors of inferior survival: age >65 years, hemoglobin <10 g/dL, leukocytes >25 × 10(9) /L, circulating blasts ≥1%, constitutional symptoms, red cell transfusion dependency, platelet count <100 × 10(9) /L, and unfavorable karyotype (i.e., complex karyotype or sole or two abnormalities that include +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p- or 11q23 rearrangement). The presence of 0, 1, "2 or 3," and ≥4 adverse factors defines low, intermediate-1, intermediate-2, and high-risk disease with median survivals of ~15.4, 6.5, 2.9, and 1.3 years, respectively. A >80% two-year mortality is predicted by monosomal karyotype, inv(3)/i(17q) abnormalities, or any two of circulating blasts >9%, leukocytes ≥40 × 10(9) /L or other unfavorable karyotype. Observation alone is adequate for asymptomatic low/intermediate-1 risk disease. Allogeneic stem cell transplantation or experimental drug therapy is considered for intermediate-2/ high risk disease. Conventional or experimental drug therapy is reasonable for symptomatic intermediate-1 risk disease. Splenectomy and low-dose radiotherapy are used for drug-refractory splenomegaly. Radiotherapy is also used for the treatment of non-hepatosplenic EMH, PMF-associated pulmonary hypertension, and extremity bone pain.

Effective management of accelerated phase myelofibrosis with low‐dose splenic radiotherapy

The main cause of hepatosplenomegaly in primary (PMF), post polycythemia vera (post-PV MF), and post essential thrombocythemia (post-ET MF) myelofibrosis (MF) is extramedullary hematopoiesis (EMH). Drug-refractory symptomatic splenomegaly in MF is usually managed by splenectomy or involved-field radiotherapy. The latter is most effective in the treatment of MF-associated bone pain and pulmonary hypertension.Our previous experience with hepatosplenic radiotherapy in MF showed efficacy in the majority of treated patients but its utility was limited by the transient nature of its benefit and the occurrence of treatment-related pancytopenia. In an effort to address these issues,we have adopted an induction-maintenance treatment strategy that utilizes lower radiation doses-induction with 100 cGy total in four daily doses of 25 cGy and maintenance with either the same or lower intensity regimen. Herein, we report our most recent experience using this treatment plan in two cases, who in addition to their expected response from the standpoint of splenomegaly, also unexpectedly showed a marked response of their underlying accelerated phase disease,including clearance of circulating blasts and basophilia.

Idiopathic pulmonary arterial hypertension in a patient with pyruvate kinase deficiency and paravertebral extramedullary hematopoiesis

Dear Editor, Pulmonary arterial hypertension (PAH) is defined as a sustained elevation of pulmonary arterial pressure to more than 25 mmHg at rest or to more than 30 mmHg during exercise, with a mean pulmonary–capillary wedge pressure and left ventricular end-diastolic pressure of less than 15 mmHg, leading to right ventricular dysfunction, congestive heart failure, and death [1]. PAH is a well-known complication in patients with hemoglobinopathies such as sickle cell disease and thalassemia. PAH is closely related to the hemolytic anemia. Nonhepatosplenic extramedullary hematopoiesis has been described in association with a wide variety of myeloproliferative diseases and hemoglobinopathies such as sickle cell disease and thalassemia [2]. It is due to increased renal excretion of erythropoietin secondary to anemia or hypoxia and can involve any organs and tissues, including the mediastinum, pleura, lungs, and heart. In most cases, the diagnosis is fortuitous, and rarely, the lesions are symptomatic, displaying neurological signs, pleural effusion, cardiac tamponade, and dyspnea [2]. Pyruvate kinase (PK) deficiency is the most common cause of hereditary nonspherocytic hemolytic anemia, transmitted as an autosomal recessive condition, with classical features ranging from mild anemia to a transfusion-dependant disease [3]. We report in this paper a case of dyspnea indicating idiopathic PAH associated with paravertebral hematopoiesis in a patient with PK deficiency. A 47-year-old man, current smoker, with PK deficiency diagnosed at birth requiring splenectomy at age 5 years and who denied any drug intake, was hospitalized in July 2007 for dyspnea on exertion [New York Heart Association (NYHA) class III] present for 1 month. On examination, he appeared healthy. A grade 3/6 systolic murmur was heard best in the pulmonary area. Mucocutaneous jaundice was found. The findings on laboratory testing of renal function, liver test function, and C-reactive protein, search for antinuclear antibodies and anti-extractable nuclear antibodies, and HIV testing were normal or negative. Hepatitis B virus serology was consistent with past immunization, and hepatitis C virus serology was positive, with a negative viral load. Other laboratory test results are indicated in Table 1. Arterial blood gas analysis showed pO2 73 mmHg, pCO2 34 mmHg, pH 7.43, SaO2 93% while breathing ambient air. Chest X-ray (Fig. 1) and computed tomography (CT) scan demonstrated paravertebral soft tissue masses extending from T1 to T10, with heterogeneous enhancement after contrast administration and main pulmonary artery enlargement at 43 mm without signs of thrombotic or embolic disease concordant with the ventilation-perfusion lung scan. Magnetic resonance imaging (MRI) displayed the paravertebral masses isointense on T1-weighted sequences, Ann Hematol (2009) 88:603–605 DOI 10.1007/s00277-008-0644-z

Agnogenic myeloid metaplasia with pulmonary hematopoiesis

Agnogenic myeloid metaplasia (AMM) is characterized by bone marrow fibrosis, splenomegaly and leukoerythroblastic anemia and is frequently accompanied by extramedullary hematopoiesis (EMH). Pulmonary interstitial EMH associated with myelofibrosis has rarely been described in the medical literature and is usually fatal. We report the case of a 77-year-old man with agnogenic myeloid metaplasia (AMM) treated with hydroxyurea, who seven years after diagnosis presented with dyspnea and severe hypoxemia. Radionuclide bone marrow scanning demonstrated increased tracer activity on the bases of both lungs, consistent with non-hepatosplenic EMH. Pulmonary EMH is rare in patients with AMM, but should be considered in patients with hypoxemia and respiratory distress.

Myelofibrosis with myeloid metaplasia: new developments in pathogenesis and treatment.

Myeloid metaplasia with myelofibrosis (MMM) is a chronic myeloproliferative disorder (CMPD) characterized by progressive anemia, massive splenomegaly, both hepatosplenic and non-hepatosplenic extramedullary hematopoiesis (EMH), a leukoerythroblastic blood smear, circulating progenitor cells, and marked bone marrow stromal reaction including collagen fibrosis, osteosclerosis and angiogenesis. The overall median survival is 5 years although it might range from 2 to 15 years depending on the presence or absence of clinically defined prognostic factors. Death is often due to leukemic transformation, portal hypertension or infection. In addition to shortened survival, quality of life is often affected by frequent red blood cell transfusions, profound constitutional symptoms, and cachexia. Drug therapy and autologous hematopoietic stem cell transplantation (HSCT) are of only palliative value and have not been shown to improve survival. The role of allogeneic HSCT, both myeloablative and non-myeloablative, is actively being investigated. Both splenectomy and radiation therapy have defined therapeutic roles to control EMH-associated symptoms. Analysis of the molecular biology of the disease is underway with the aid of animal models leading to the identification of novel therapeutic targets. Among the novel agents tested, thalidomide seems the most promising although newer agents are on the horizon.

Nonhepatosplenic Extramedullary Hematopoiesis: Associated Diseases, Pathology, Clinical Course, and Treatment

To define associated clinical conditions, pathology, natural history, and treatment outcome of nonhepatosplenic extramedullary hematopoiesis (NHS-EMH). We retrospectively reviewed the medical charts of all patients identified as having NHS-EMH from 1975 to 2002. Diagnosis was made by tissue biopsy, fine-needle aspiration biopsy, or radionuclide bone marrow scanning. We identified 27 patients with antemortem diagnosis of NHS-EMH. The most common associated condition and disease site were myelofibrosis with myeloid metaplasia (MMM) (in 18 patients [67%]) and the vertebral column (in 7 patients [26%]; all involving the thoracic region), respectively. At the time of diagnosis of NHS-EMH, concurrent splenic EMH (in 22 patients [82%]; 15 [56%] had undergone splenectomy) and red blood cell transfusion dependency (in 12 patients [44%]) were prevalent. Of the 27 patients, 9 (33%) required no specific therapy. Specific therapy was radiation (in 7 patients with a 71% response rate) and surgical excision (in 6 patients with a 67% response). Treatment-associated complications were limited to surgery. Radiation therapy was not used in the non-MMM group, but low-dose radiation therapy was used in the MMM group for paraspinal or intraspinal EMH (median dose, 1 Gy; range, 1-10 Gy), pleural or pulmonary disease (median dose, 1.25 Gy; range, 1.00-1.50 Gy), and abdominal or pelvic disease (median dose, 2.02 Gy; range, 150-4.50 Gy). Median survival after the diagnosis of NHS-EMH was 13 months in the MMM group and 21 months in the non-MMM group. This retrospective study suggests that NHS-EMH is rare, is often associated with MMM, and preferentially affects the thoracic spinal region. Asymptomatic disease may require no specific treatment, whereas symptomatic disease is best managed with low-dose radiation therapy.

The forgotten myeloproliferative disorder: myeloid metaplasia.

Myelofibrosis with myeloid metaplasia is a hematologic disorder currently classified with polycythemia vera and essential thrombocythemia as a chronic myeloproliferative disease. The median age at diagnosis is 60 years, and more than 90% of patients are diagnosed after age 40 years. Clinical manifestations include massive splenomegaly, progressive anemia, profound constitutional symptoms, and extramedullary hematopoiesis. The diagnosis is confirmed by bone marrow examination after other causes of myelofibrosis are ruled out. Median survival is 5 years and causes of death include leukemic transformation. Prognosis is adversely affected by the presence of anemia (hemoglobin <10 g/dl), leukopenia or leukocytosis (white blood cells >30,000/ micro l), circulating blasts, and hypercatabolic symptoms. Conventional treatment is palliative and does not improve survival. In this regard, androgen preparations, corticosteroids, and erythropoietin are useful for the treatment of disease-associated anemia. Symptomatic splenomegaly is best managed by cytoreductive therapy or surgical removal. Radiation therapy is most useful in the treatment of nonhepatosplenic extramedullary hematopoiesis. New treatment approaches include the use of thalidomide alone or in combination with prednisone and hematopoietic stem cell transplantation.